Breakout Session A Summary: Antiangiogenesis Agents: Therapeutic Directions by Paul Bunn Jr, MD

SLIDES & TRANSCRIPTS
Thursday, June 15, 2000

Breakout Session A Summary: Antiangiogenesis Agents: Therapeutic Directions
Paul A. Bunn, Jr., MD

Slide 1:

DR. BUNN: I wasn't sure why I was asked to chair this session, because I know nothing about angiogenesis. I must admit, after spending the afternoon in the session, I still know nothing about angiogenesis. But I learned that nobody else knew anything about it as well. That's why Wally is in parentheses on the session title slide. He wasn't even there. But Scott Saxman was able to fill in nicely.

Slide 2:

So there are a large number of agents being studied. The first couple of slides just actually are compilations of what actually is going on, some of which is still incorrect here. But one of the major points of the discussion was that since there are a limited number of patients that are going to go on studies, how does one select which agents are going to go forward into Phase III trials, because there are limited numbers of resources.

So just to give you a flavor for how many different compounds there are, there's a little bit of a list here. So if the target is VEGF over-expression, there are studies in lung cancer going on with Sugen small molecule SU5416, specific to lung cancer. This is Genentech's anti-VEGF antibody, which has completed randomized Phase II data, and is being proposed for Phase III trials. Marimastat has completed randomized Phase III trials, and in fact is more than three years out from the randomized Phase III trials, and the Data Safety Monitoring Board has not said that the data should be disclosed yet.

AG3340, an MMP inhibitor from Agouron has completed a randomized Phase III trial with carboplatin and taxol and is in Phase III trial with gemcitabine and cisplatin in an ongoing trial. The Bayer compound 9566 was in a randomized trial for maintenance treatment of small cell lung cancer. The trial was closed because the survival was worse in the patients that were receiving the Bayer compound. That caused the closing of the trial, and a lot of skepticism about MMP agents. We had a very long discussion yesterday, as well as several discussions in previous meetings about how one should interpret that.

And we saw data from several companies yesterday that the MMP inhibitors are actually quite different. They inhibit different enzymes. The targets are different. The amount of protein binding is different. The toxicities are different. I would say that the general feeling was that one should not stop the development of any of these other MMP inhibitors because of the results with Bayer. And we can discuss that some more when I finish.

Slide 3:

Randomized Phase III trials are also going on with CAI, with thalidomide, and with neovastat, a shark cartilage extract. So there are in non-small cell lung cancer, at least three ongoing randomized Phase III trials, that were designed and started at varying different times.

In fact, we were trying to develop some criteria for where to go forward. When we looked back at some of the agents that are in clinical trials now, we would say, well, if we used the criteria that we are sort of proposing, many of these agents got into Phase III trial without criteria that we would be proposing now.

Endostatin and angiostatin aren't in lung cancer-specific trials yet. They are in Phase I. Squalamine is in a lung cancer trial, I think just starting Phase I.

Slide 4:

As for other compounds looking at VEGF over-expression, the Sugen compound is not in lung cancer-specific trials yet. A couple more compounds in Kaposi's sarcoma trials. Angiozyme, which is a ribozyme to the VEGF receptor is being proposed for Phase II lung cancer trials, and a compound from Zeneca in Phase I studies.

DR. MABRY: Paul I'm sorry, about Sugen SU6668—it’s in phase I clinical trials.

DR. BUNN: Oh, I'm sorry. Phase I is what I actually meant.

Slide 5:

A number of agents to the alpha-5, beta-3, or beta-5 receptor. And then other of other MMP inhibitors that haven't yet been studied in lung cancer, but are being proposed, again with different MMP’s as their targets, and different amounts of protein binding, some for specific MMP’s and some for a much broader range of MMP’s that they inhibit.

Slide 6:

So if you were to add up all the compounds that you just saw and say we were going to do randomized Phase III trials that had 600 patients in each, you can understand that there aren't enough patients to study the antiangiogenesis inhibitors that we have, let alone the agents discussed in Workshop 2 and 3.

So then we had a long discussion about, what do we do? How do we decide? What are the criteria for deciding? And what are the types of studies that should be done? In lung cancer we had the debate first of all about tissue. We actually started out the debate about tissue talking about microvessel density. Microvessel density is actually an interesting biomarker. It has been well established in multiple trials that it has prognostic relevance. It has been established that it is in multivariate analysis, an independent prognostic variable in essentially every study, but there are a couple problems.

First of all, the methods for assessing microvessel density vary all over the map, and there is no standardized method whatsoever. Whether you can predict whether an antiangiogenesis agent will work based on the microvessel density is an interesting hypothesis for which there is absolutely no data, but which would be interesting to obtain.

A problem that Ned Patz was mentioning, this is probably not reliable from a fine needle aspiration. And so the question is, how can you get a piece of tissue before and after? And we had a discussion about an example, Stage I lung cancer, where most patients are going to the operating room without any tissue before they go to the operating room, or with at most, an FNA. One of the conclusions was that lung cancer is probably a poor model for looking at actually optimizing the target for angiogenesis inhibitors. Perhaps melanoma and some other head and neck cancer might be much better models for looking at a target when you need an invasive measurement.

So we had a considerable discussion about that. And then because of that, we felt that studies to determine the best imaging modalities for selective targets were quite a high priority. Of course the problem is what will be done to study the antiangiogenic inhibitors clinically before we get the model systems worked out?

We just had that discussion, so I won't dwell on this, but people thought obviously it would be really a lot easier to do these clinical trials if we had some noninvasive test. As you heard earlier, the problem is there isn't a known good test.

Another interesting thing is that people want to determine the optimal biologic dose by actually assessing molecular or biologic targets. The problem is there are very few standardized tests for actually looking at these targets. For example, if you want to know whether the microvessel density changes, what standardized test do you do? If you want to know whether you change the VEGF receptor, what test do you do? If you are looking at something that is phosphorylating a protein, what standardized test do you do? And some of these tests are important enough that there probably should be some standardization.

Slide 7:

Then we discussed selection criteria for Phase III trials based on a couple of things. The first is safety. I'll begin by saying that people were somewhat impressed by the toxicity of some of the agents, which led us to conclude that really Phase II trials need to be done before launching into Phase III trials, because of unexpected toxicities that have developed with the agents that we know about.

Two of the examples that we discussed were the unexpected pulmonary hemorrhage from anti-VEGF antibody, along with other bleeding episodes with anti-VEGF. There are strokes and neurologic sequelae of the SU5416 compound, and these I think led people to be highly suspicious of this idea of going from Phase I trials directly into randomized Phase III trials. In fact, the group recommended that the NCI not do that with this class of agents.

The next thing that we discussed with respect to safety was that complications with thoracotomies are not adequately studied by looking exclusively at wound healing. The feeling, especially of the surgeons in the group, was that anti-angiogenic trials for patients with Stage I to Stage IIIA that involve a thoracotomy, at the moment should not be done with any anti-angiogenic compound that anybody in the room knew of, because nobody knew of any preclinical safety data demonstrating that it would be safe to do a thoracotomy after one of these agents.

The group basically encouraged companies developing these compounds to use animal models with surgical resections to make sure that the healing and bleeding after a large operation are not changed by these agents. This did not mean that these agents should not be studied in melanoma or something where the consequences are much less. The feeling of the group was that no anti-angiogenic compound at the moment has been shown to be safe for patients for who are going to undergo a thoracotomy.

We had a long discussion about whether it is important, possible or reasonable to try to determine the MTD of these types of compounds. The feeling was in general, if you have an idea what toxicity you might be getting, it might be reasonable to actually try to obtain an MTD. But there was some recognition that that probably won't always be possible.

Certainly everyone wanted to get pharmacokinetic and pharmacodynamic measurements before entering Phase III clinical trials. We had a fair amount of discussion about what some of the endpoints were. And certainly there was some data with MMP inhibitors suggesting that staying above a certain concentration for a long period of time was an important variable. But knowing the pharmacokinetics and pharmacodynamics was felt to be very important.

Then of course, we spent the most time for both safety and efficacy talking about the optimal biologic dose for any given target. And how to determine the optimal biologic dose is, of course, a considerable challenge and will vary by the target. I'll come back to that a little later.

Slide 8:

Most of the Phase III trials that we discussed were actually combination studies; largely combinations with other drugs for Stage IV patients, and largely combinations with other drugs and radiation for Stage IIIB patients. So it was felt that for safety considerations before launching into any randomized trials, one would have to have drug-drug interactions, and drug-radiation interactions known before launching into a Phase III trial. Of course, besides whether you change the pharmacokinetics, one would want to know with respect to schedules and timing, what was predicted to be the optimal way of doing this, and whether the schedule and timing would affect toxicity, as it does for many, many agents.

We discussed specific issues based on preclinical and early clinical studies, and many of the safety issues have been unexpected. It was felt that one has to be very circumspect about looking for safety issues with these compounds, because a lot of unexpected toxicities have cropped up.

We had a long discussion about whether basically you could use data from other cancers to direct what you should do in lung cancer. In other words, if there is a lot of data about pancreatic cancer, is that justification for launching into some trial in lung cancer? And largely people felt that we really should be basing Phase III trials in lung cancer on data from Phase II trials in lung cancer, for a variety of reasons. One is that these patients have a lot of co-morbid conditions that are different from other disease. Angiogenesis in this disease is likely to be different than other diseases. And so largely the group actually has the same feeling as the FDA on this issue, that most compounds in early development are somewhat cancer-specific.

Slide 9:

Looking at efficacy considerations, we had a little bit of a discussion about preclinical studies, and in general people felt that although there is not a great correlation between what happens in rodents and what happens in humans, people felt that for these particular agents it would important to know what happens in human lung cancer xenograft models before launching into human lung cancer trials.

People felt it was very important in preclinical studies with respect to the target, this is an area where you can get tissue, and you can get tissue sequentially. For many of the compounds that have actually gotten into Phase III trials, there is very little information from preclinical studies about what is the optimal biologic dose, and that should be assessed.

Pharmacokinetics and pharmacodynamics should begin in the preclinical models, and the scheduling issues can also be started in the preclinical models.

Slide 10:

So again, for efficacy in terms of clinical studies, it was felt that trying to determine an optimal biologic dose should be done, and we'll get into some specific examples of when obtaining the PK and PD should be done. And it was felt that before launching into a Phase III study in lung cancer, one ought to know, or have a clue as to what happens to response, time to progression, and survival. Once again, there are many compounds in Phase III trials for which none of this information is even close to resembling anything useful.

Slide 11:

So this might be controversial, but anyway our group felt that Phase III studies with anti-angiogenic agents in lung cancer should require feasibility and safety data from Phase II studies. With respect to efficacy, and this was highly debated, the Phase II studies ought to suggest that the agent at a minimum is not worse than what you would expect with whatever you are combining it with alone.

And there ought to be data suggesting that the agent is better before moving to a Phase III trial. Something better might be a longer time to progression. It might be a better survival. It might be higher response rate. But if all those were seemingly the same, it might be some evidence that you are actually affecting your target in an optimal biologic dose way. Once again, many of the agents that are in current clinical trial do not come close to meeting these criteria. And the question is whether these criteria help us select from the 20 or 25 that are remaining, as to which ones are going to get into clinical trial?

Slide 12:

Feasibility, it was felt, was minimal if agents seemed equal with respect to whether they should go into clinical trial. People thought maybe the route of administration, convenience, toxicity issues might be important, but were not actually quite minimal.

Slide 13:

So we talked about two examples. Hak Choy was kind enough to provide us with some food for discussion by giving examples. One study was useful. This was a proposed study where he was proposing to get biologic endpoints by obtaining tissue biopsy, then giving this compound with chemo and radiation -- this is for Stage IIIA patients -- and then resecting them. Once again, the surgeons felt that this study should not be submitted to any IRB, because of the lack of safety data, and the effect that these compounds could have on the thoracotomy, that there is not sufficient safety.

Of course then Mike brought up again the issue as to how do we determine then if you can't do surgery, and the only way to get tissue to look at is surgery, how can you ever develop the optimal biologic dose? And again, that's why we got into the discussion of imaging agents and so on.

Slide 14:

Then we discussed a study that was for IIIB, for inoperable patients, a study that didn't have surgery. So obviously this doesn't have the tissue studies. And the idea was to combine this compound with chemoradiation, and then this compound with chemotherapy after concurrent treatment. What was discussed here was how do you know when you get done with this, what the dose and schedule that you should be using is? Because if you don't have tissue, how is the optimal biologic dose determined? And how will you pick the dose to go into a Phase III trial or even a Phase II trial when you get done with this?

So now we are going to turn to discussion.

Slide 15:

DR. WILLEY: In terms of tissue, how much tissue do you think is required in this situation? I mean a fine needle aspirate is certainly feasible. But are you thinking more tissue than that is necessary?

DR. BUNN: For many markers an FNA would work. If you need to measure phosphorylation, or you have some antibody test, a histochemistry test that could be done, an FNA would work for some targets. If you need something like a microvessel density, an FNA is probably not going to suffice. So there probably are some targets for which an FNA would work.

DR. WILLEY: I'm just thinking that until the imaging capability arrives, which we are all obviously anticipating, we need to do what we can with the samples we can get. So that means now fine needle aspirates.

DR. BUNN: Yes, just a comment. If you look at any neoadjuvant study, after treatment it takes the pathologist hours to find the viable tumor cells that are left after neoadjuvant treatment in the majority of patients. So I think one of the conclusions that Gail Eckhardt and others suggested was that many of these optimal biologic dose trials are probably going to need to be done in other models, the preclinical models of lung cancer before we get to these studies and other tumors, because they are going to be very difficult to work out in lung cancer patients. Ned, how often do you get viable tumor from an FNA after neoadjuvant treatment?

DR. PATZ: The real answer is we don't do it very often, so it's very hard to say. But again, once you are dealing with somebody who often has IIIB disease, and it is very difficult to know where to go, and we have to make multiple passes. So it's not trivial. We can do it, but it's not such an easy thing to do.

DR. MABRY: Paul mentioned toxicities of the angiogenesis inhibitors. I think for the record, so folks don't walk away with any false impressions, the actual numbers are that SU5416 has been given to 350 people as of yesterday. We had two people who had cerebral vascular accidents, which occurred in a lung cancer pilot with gemcitabine/cisplatin. One other patient had in the setting of hypertension, had mental status changes which resolved. And a third patient had right leg weakness, which also resolved. So those are where we are with that, and those are the things that we have been seeing with 5416.

DR. BUNN: Unfortunately, Jeff Humphries from Bristol isn't here, but he sent us some data about marimastat. Many of us in lung cancer don't know what happens in other diseases. Recently in the public domain is information about marimastat in randomized trial in pancreatic cancer, three doses of marimastat, 5, 10, and 25. There was a clear dose response, with the higher doses doing better. And in fact the highest dose was equivalent to gemcitabine in the randomized trial.

There was another trial with marimastat in gastric cancer where marimastat was actually associated with a prolonged survival. The original p value was 0.07, but with longer follow-up it's actually 0.05.

So I only bring that up to again alleviate fears about the Bayer study. And of course, unfortunately, in the public domain, we don't actually have any information about the Bayer study. But I think in general people felt that the MMP inhibitor should continue with investigation.

DR. GANDARA: Paul, I know that Bayer has also sent data to CTEP regarding their trial in non-small cell lung cancer, which was going on at the same time as the trial in small cell lung cancer. When the small cell lung cancer data proved negative, they closed the non-small cell trial. So it didn't reach its targeted sample size, however, in their analysis of the data the trend, and a fairly strong statistical trend, is in favor of their compound improving survival in non-small cell lung cancer. So it again raises the issue of whether even their compound is tumor-specific for the biologic effects, or whether the small cell trial is a false lead. I know that data has been sent to CTEP.

DR. BUNN: Frances?

DR. SHEPHERD: I just wanted to give you an update on where the NCI EORTC trial in small cell lung cancer with marimastat stands. That trial was originally designed to detect a 50 percent improvement in overall survival after chemotherapy. The pharmaceutical firm itself had done another trial, and closed the first trial. I think they probably realized they had been overly optimistic for the agent, and so we were asked to expand our trial, which was still ongoing.

So it's not a very large trial. It closed with 560 patients in it, which will certainly be the largest trial in any of these MMPI studies to date in small cell lung cancer. It finished in April, so knowing what small cell lung cancer is like, we should have data around the end of year, and certainly by ASCO next year. But at the data and safety monitoring boards that were done for this regularly, there was no evidence of toxicity or poorer survival that would lead to the study being closed early.

DR. BUNN: For those of you that don't deal with lung cancer every day, Bruce Johnson did a nice review of the literature for ASCO this year. Of the last 54 randomized trials in non-small cell lung cancer, a survival difference of two months or more has been noted in two; 2 out of 54.

The number of trials that were powered to show a two-month difference in survival was less than 5 out of the 54. So essentially all the trials are underpowered. If we are looking for a reduction in hazard rate of death, which is the primary endpoint in essentially all these trials, if we are looking for a 30 percent reduction, the sample size is close to 700. And again, that is why the discussion we were having yesterday was important. When you are talking about putting 500-700 patients on these randomized trials, which is the size they should be, resources are precious.

DR. SAUSE: Paul, do we have any anecdotal data about surgical toxicity with these agents? Theoretically it would be a hazard to do surgery in these patients, but are there patients that have had appendectomies or incident surgery where there have been wound problems, or anything to make us think that it would be hazardous?

DR. BUNN: Well, I'll ask Jim Pluda to answer that question, or Gail Eckhardt. Gail, Jim?

DR. PLUDA: I don't like to say any more if I'm not aware of things.

DR. ECKHARDT: Yes, I don't think in the trials that we have done, that we had patients that went to major surgery.

DR. BUNN: My understanding is there is very little information about that. Certainly the toxicities are different for the different agents. Maybe Dr. Mass can talk a little bit about the bleeding and the pulmonary bleeding from anti-VEGF.

DR. MASS: I think many of you probably saw the presentation at ASCO. While we treated 90 patients in the lung cancer trial, and in the two active arms, two different doses of anti-VEGF antibody, and saw six life threatening pulmonary hemorrhagic events in the anti-VEGF treated groups, four of which were fatal. The predominant risk factor appeared to be squamous cell histology in a central location.

The way those trials were designed, the patients who did not receive the antibody in the control arm were allowed to cross over to get antibody after progression, and we didn't see bleeding in that group. Again, the other bleeding findings that we saw were general mucosal hemorrhage that we've seen across all of our anti-VEGF studies, not only in lung cancer, but in colorectal cancer, breast cancer, prostate cancer, and renal cell carcinoma.

We have very little data on surgical risk, Paul. There are one or two patients who have had some minor surgical procedures, catheter insertions, that sort of thing, without untoward complications, but no major surgeries that I'm aware of in the anti-VEGF trials.

DR. BUNN: Dr. Collier, do you want to say anything about MMP’s and bleeding?

DR. COLLIER: With the MMP’s and bleeding, there aren't any bleeding events that I know of with our agent. So that is not one of the manifestations of the drug. But we do have many patients in Phase III trials. We have three Phase III trials currently open. Among them we have had some patients go on to hip replacements while taking the drug. Of course they are blind to trial, so whether they are on placebo or not, is not known.

And among the patients who have had these kind of unscheduled procedures, we don't have any reports of untoward events afterward. So another element that we should remember is that if the agents have a short half life, and are stopped sufficiently far in advance of surgery, it is quite likely that they will wash out and the drugs will have no effect at the time of surgery.

DR. BUNN: The feeling was that these are answerable with preclinical models, and why not require that some preclinical data be obtained? It wasn't felt to be all that big a deal to try to get some preclinical data.

DR. SAXMAN: Let me ask this group a question, because it is interesting to me the trend over the past few years I think has been to sort of a move away from Phase II studies, the idea being with some of these agents, because of the unique mechanisms and the cytostatic effect that Phase II studies don't tell as much as they used to.

I was at the ASCO meeting a few weeks ago. Jamie can attest to this. The argument was made to me that we should randomize the first patient. Yesterday's group, as Paul mentioned, felt very strongly that we still have much to learn from Phase II trials, and that we actually should not embark on Phase III studies until we have defined many of these things in Phase II trials, in spite of the fact that we have done that, and there are some proposals coming from the groups and from other investigators that are still proposing to do that. I guess I just wanted to make sure that this group felt as strongly about that as the breakout group that we had yesterday. I'm not hearing any dissension about that. I personally agree with that point of view, but I was just interested in whether anyone else had any other opinions.

DR. SHEPHERD: We discussed that in Group 3 as well, and I think it was our feeling that Phase II studies were still needed. It was felt that patients that were put on Phase I studies often didn't stay on the drug for very long, either they might be sick and have progressive disease very early -- there are some centers that just keep rolling patients from one Phase I study to another every two cycles. If there isn't a response, they move them on to the next Phase I.

You really only have a very small snapshot of a short number of cycles in a rather poor patient population. So it was felt quite strongly in our group that we really did need Phase II, if for no other reason -- well, among other reasons, to get more long-term toxicity data on some of these agents, particularly since some of the patients we might expect in early stage of disease, to stay on these for a long time.

DR. BUNN: That was exactly the sentiment in our group. Some of these toxicities that Dr. Mass just talked about, occurred very late. The patients haven't been on for that long a period in Phase I trials.

DR. GANDARA: However, there was a minority report in Frances' group. The issue is not whether we need Phase II trials, but how many do we need? They are overdone. And we don't need 20 Phase II trials done at many institutions around the country before we make a decision to go to Phase III. In particular, the recent use of randomized Phase II trials I think has been detrimental for the large part, rather than helpful, because in many instances they have been interpreted as Phase III trials, when the sample sizes are not designed to really compare the two regimens.

The issues about Phase II I think are also most important where you have toxicity problems that you are trying to deal with. For some of the agents that are relatively non-toxic, then limited Phase II trials moving into Phase III is probably appropriate as long as you have some sort of long-term follow-up data on some patients.

DR. BUNN: How do you know that? That was a big point of discussion. When you say that you know the agent is safe, after Phase I, how do you know the agent is safe?

DR. GANDARA: Compare this to chemotherapy. What have we been doing for 20 years with chemotherapy? These agents are different, but in chemotherapy we don't require some patient being followed for five years after getting taxol before you do a randomized Phase III trial employing taxol.

DR. BUNN: Well, we don't have a lot of agents. Four out of 30 patients or 4 out of 60 patients is not a trivial number to die from an unexpected toxicity.

DR. GANDARA: That's why I said toxicity is really the issue. And for the antiangiogenic agents, it is probably a more pertinent issue than it is for some of the others.

DR. BUNN: Okay, I see what you are saying.

DR. PLUDA: I guess the other thing that came up when we discussed Phase II studies is you said you don't need 20 Phase II studies. If you've got a number of Phase II studies demonstrating interesting activity or biological activity, and indicating safety in diseases other than lung cancer, do you still need to go back and repeat the lung cancer Phase II studies? That was a point of discussion in our group, and the consensus was that, yes, even though you may have a number of other Phase II's in renal or colon or pancreas or gastric, with safety data and biological activity, there was still a need to go back and do specific lung cancer trials as well. I would like to hear what the rest of the group feels.

DR. BUNN: That was largely because of the anti-VEGF experience, where the toxicity in lung cancer was not noted in any other disease.

DR. SCHILLER: I think it's important to differentiate the goals of a Phase II in these settings. It sounds like we are talking a lot about the major goal of a Phase II trial as being toxicity, contrasted to efficacy, which has typically been the standard goal of Phase II studies. In general, we have used Phase II trials to determine whether or not the drug is clinically interesting enough for further development. I think it's hard to see how we can do Phase II's in this setting with that as a major endpoint contrasted to toxicity.

DR. BUNN: The group actually felt that it was dual, that it was both. The group felt the Phase II trials were needed for both. And again, part of that is because of other experiences that happened. Remember, even though the Bayer compound was one of the ones that went from Phase I to Phase III, it was harmful. Now whether you would have known from a Phase II that it was harmful, we don't know. But we know that going from Phase I to Phase III wasn't a good idea.

DR. SCHILLER: Paul, what did your group feel would be a good efficacy endpoint for a Phase II -- response rates, time to progression?

DR. BUNN: It would depend on the study design, but there were three endpoints that were discussed, and it was felt to be different, depending on the agent in the trial design. Obviously, if you were looking at a maintenance type of design, you wouldn't be looking at response rates. So the three that were discussed of course were response rate, time to progression, and survival. We didn't make any recommendations, because we thought it would depend on the agent and the trial design.

DR. SCHILLER: One of the problems with a Phase II which has limited numbers of patients though is that coming down with good confidence intervals around the time to progression and survival is problematic.

DR. BUNN: Right. And we had a statistician from the NCI in the room. We certainly didn't come up with a recommendation. But again, even if the results were the same as seen in previous studies, the odds in a big randomized Phase III that you are going to be better is not high. But what we ended up saying was that the phase II results should not be worse, and something that looks positive.

DR. ALBAIN: I think to follow-up Jim Pluda's comment, we also commented that many of these trials were being designed with combined modality, and that might be why lung cancer-specific data would be indicated. If you just had single agent data or the new agent combined with a chemotherapeutic agent in another disease, it may not be the same as combining it with drugs that are known to affect angiogenesis, such as the taxanes and radiation, and the new agent, all as trimodality design. You would want lung cancer-specific data, I thought was our consensus.

DR. BUNN: Right.

DR. CURRAN: This issue is really critical as a recommendation to the lung cancer concept evaluation process, because following up on what Kathy said, let's suppose you even have encouraging Phase II data in metastatic disease with chemotherapy and a new agent. Does that mean that you don't need bimodality Stage IIIB data before you got to the Phase III? And going back to what Joan said, let's say Stage IIIB disease. We now have median survival times in Phase III studies of 17 months. Do we need to have Phase II data with this new agent chemoradiation of let's say 21 months before the CEP approves the next big Phase III trial? That's part of our responsibility today, to kind of advise Scott and that panel as to what our opinion is.

DR. SAXMAN: What is your opinion?

DR. CURRAN: I think for Phase II data we should see something better than the established standard before we commit 800 patients to the next trial.

DR. BUNN: That was the feeling of the group. A side issue was there was a feeling in our group that the panel's final conclusions, not the panel discussions but the final conclusions of the panel, and the reason for their decision should be in the public domain. Because certainly up until now, the playing field hasn't been level in this particular field. Nobody was really critical of that, because many of the compounds that are in study, the studies were designed at a different time. But certainly many of the compounds that are being studied now don't meet these criteria. And certainly compounds that come close to meeting this criteria have been turned down. And so just to keep the playing field level, there was feeling that those panels' final decisions should be open public knowledge.

DR. CURRAN: That may be why we have so many negative trials as well.

DR. ABRAMS: I was at this session too, and I would like to say that I think it was discussed, but I don't think there was a consensus on that viewpoint by any means. You know we didn't actually want to discuss it at that forum, because we wanted to stick to the science. But since Paul brought it up, I think it's important to point out that I don't really think it's the NCI that has any problem with these things becoming public.

I'm sure it would be the investigators and their designs and their research that they have been working on to try to get these proposals from the laboratory to the clinic. That would be a big problem. And I could see how that would really hinder them, and there would be a lot of fear that their ideas would be perhaps taken by others.

So it is a little bit different than the FDA forum, where there are patent rights and things are public when they finally come in for their filing. Here we are a much earlier stage of research. One of the things that often happens, not infrequently at concept evaluation panels, is people are given ideas to modify their proposal, and they want to go back and work on it then. They don't want the whole world to then take their idea and run with it before they have a chance to make changes. So without wanting to harp on this subject, I think that it is a little bit different than an FDA filing.

DR. CHRISTIAN: I would like to follow up on that, too, because I think that as we discussed in the group yesterday, the concept evaluation panels are following a traditional peer review model, where the privacy and confidentiality of the data that is reviewed, and of the review process is one that is respected. And those documents are not disclosed.

I think with regard to a level playing field, that is such a complex issue, as we also discussed, Paul. Many of these studies come from industry. They come from individual groups and centers that have a major role in determining design as well. So I think it's really important for this group to voice its views of the most appropriate ways to proceed. But I think that there are many, many factors that go into the kinds of designs that are eventually proposed and reviewed, and approved or not approved. It's a very complex process.

DR. BUNN: Yes, and I probably shouldn't even have mentioned it. I don't think people really wanted the details of background information. For example, this wasn't necessarily my discussion, but several concepts with these compounds have been forwarded. For example, one of the MMP’s was brought forward for a randomized Phase III trial in Stage IIIB, and it was not accepted. So the question is for the next person that wants to come along with a randomized trial in Stage IIIB, what are the criteria for which that compound will be accepted or not accepted? Presumably, one of the criteria would be that it wouldn't look anything like the Bayer compound, but what are those -- that's sort of the issue.

DR. CHRISTIAN: So let me follow up on that by suggesting that you are, as a group, suggesting some reasonable standards for assessing those kinds of agents in the future. And I think that's appropriate. I don't think the deliberations of a peer review group for a specific compound in a specific clinical trial proposal are going to be any more helpful than thinking carefully through what the issues for development generally are.

DR. BUNN: I hope that what we have come up with today will actually be looked at by that review panel, and commented on by the review panel. I'm not sure it's perfect, but certainly the review panel is highly likely to get some more of these. It might actually take a look at these recommendations to see how it fits in with what it's doing.

DR. SHEPHERD: There is perhaps some other route that could be taken that we are going to pursue in NCI Canada with Bristol Myers with their MMP inhibitor. I don't know if there is anyone here from Bristol Myers, but they are doing a study that is very similar to the studies that have been done by Agouron. They are doing a taxol/carboplatin plus or minus their MMPI, but the study is designed to be Phase II-III. And the Phase II part of it is randomized. And it will be exactly the same as the randomization for the Phase III, but it has distinct early stopping rules -- which I don't have in my head what all of them are at the moment -- but distinct early stopping rules based on toxicity, or any evidence of inferiority with taxol/carboplatin when combined with the agent. And this at least allows us to move into Phase III, but not have lost all that time of the Phase II study. It will save, I think, no less than a year to get the Phase III study up and running by rolling the Phase II into the Phase III, with very careful early stopping rules at Phase II.

DR. PLUDA: That's actually something that we discussed yesterday, and I think it was a matter of semantics whether you call it a Phase III study with an early interim analysis and early stopping rules, or a Phase II/III study of the same thing. But that is a design that we discussed yesterday that I think the panel, although we may not have come up with a consensus, at least looked favorably upon.

DR. BUNN: Actually, Valerie, I didn't see you here before. Do you want to comment on what kind of data you would like to see from preclinical studies before operating on patients? Do you have any comment you want to make about that?

DR. RUSCH: Actually, I think Kathy has addressed this before. In terms of evaluating in a step-wise manner, the potential risks of combined modality therapy and surgery is just one aspect of combined modality therapy. So that I think it was our consensus yesterday that it's very important to do this, not slowly, but certainly in a careful step-wise manner before moving these agents directly into induction therapy settings where you potentially run some very substantial perioperative risks. And it was our feeling yesterday that we are really lacking both a lot of clinical and preclinical information about that approach to treatment. I think that's a fair summary. Would you agree with that, Paul?

DR. BUNN: I agree with that.

DR. WONG: This is where I think, as Dr. Coleman mentioned to you folks, that we are developing the RAMEM program, which is the Radiation Modifier Evaluation Module that should be hopefully upcoming within maybe even the next year. This is where we will be have various compounds that are in the developmental stage that need preclinical data in vitro, and more importantly I think, in vivo data in terms of exactly what the angiogenesis compounds are lacking in terms of in vivo. So that we can probably provide that service to answer those questions in which the drug companies are not or do not have an interest in doing it, especially combined with radiation. So any of the novel agents that are being proposed for clinical trials, if there are any of the preclinical data that is actually missing, NCI will be the forum for where we can do those studies and get that data, so that we can then prioritize which compounds can then go into Phase III clinical trials.

DR. BUNN: I really felt that it is actually necessary. And in fairness to Dr. Choy, before we discussed Dr. Choy's protocol for the Sugen compound, he showed us some nice preclinical data, combining radiation with the SUGEN compound with and without drug. So for many compounds those data are available, and we think it's appropriate that it does become available for all these things.

DR. SCHILLER: Paul, I don't mean to harp on the slide that you have got up there, but I think this is an important point here in terms of the recommendations of your committee, because I think these recommendations will be taken very seriously. The design for a Phase II study with a major endpoint is feasibility and safety. Your first point would be much different than a design for a Phase II study where the endpoint is efficacy. The patient numbers will differ a lot.

DR. BUNN: Yes. Again, we didn't pick numbers, but I think the discussion that we had before about the Phase I studies where patients are treated for a very short period of time, two cycles, and very few patients are treated for extended periods of time, whereas, in almost all of the randomized Phase III trials, patients are treated for an extended period of time, it was felt that that is dangerous.

DR. SCHILLER: So what you were primarily recommending was feasibility and safety, as contrasted to efficacy from a Phase II study.

DR. BUNN: That's why the first one is bolded, and the second one isn't.

DR. SAUSE: What is efficacy for some of these agents? I mean our traditional endpoints like response rate and survival, are those really the endpoints we want, speaking to Joan's point, or do the agents do biologically what we say they are going to do? Is that really the endpoint? Do you have markers to say they actually do inhibit angiogenesis in the patient? Is that the endpoint?

DR. BUNN: Again, we didn't discuss this specifically, but I'm not sure that anybody on the committee, or anybody in this room, or anybody at the FDA doesn't think that survival is the most important endpoint. But if you pick a group that you think is going to have an eight-month median survival, and you do a study and you get eight months or nine months, obviously there is not going to be great enthusiasm for going to a Phase III trial.

On the other hand, if you got nine months, and you actually showed that you were inhibiting your target, this group would feel that was something positive that would give some weight to moving on to the Phase III trial. Whereas in fact if you got eight months, and you didn't have anything, you didn't have a clue what you were doing, and whether you were doing it or not, that would not lead to increased enthusiasm. So that's a bit gray, but we didn't have a black and white answer.

DR. SAXMAN: We only have another minute or two. One of the things that came up at the very end of the session, that you may want to comment on Paul, or Eva, was the possibility of looking at these agents as chemopreventatives, probably not in the classical sense in terms of preventing the oncogenic or the malignant phenotype, but as a way of preventing the clinical development of malignancy in patients who are at high risk.

I don't know if you want to comment on that further. Eva Szabo is here from the Division of Cancer Prevention at the NCI. Whether any of those things are planned, whether there will be any interest in those types of things, whether that is an avenue to take this class of agents as well.

DR. BUNN: For those that haven't followed the pre-neoplasia field, there is a very nice article in Clinical Cancer Research this month about what is called angiogenic squamous dysplasia, which shows that angiogenic lesions occur very early in the development of lung cancer. And that's a biomarker that can be followed.

There is a group called the lung cancer biomarker and chemoprevention consortium, funded by the NCI that had a discussion about the next series of cooperative chemoprevention trials. What the group actually ended up selecting as their number one, two, and three recommendations for agents to be studied was EGF receptor antagonist as number one, farnesyltransferase inhibitor as number two, and COX inhibitors as number three. A lot of that has to do with the issue of safety of long-term administration. One of the issues for these anti-angiogenic agents is the safety with long-term administration. So I think the target is a good one, and I think there will be more enthusiasm for this as more safety data from prolonged administration becomes available.

DR. SAXMAN: Eva, do you want the last word?

DR. SZABO: I think I would like to echo what you just said, which is that in chemoprevention we are really looking at patient populations that although at high risk, are primarily healthy. One of the overarching issues for us in development of drugs is clearly safety issues. Because you are taking people who are not yet sick, whether they have recovered from their resection for their Stage I lung cancer or whether they have dysplasia or are at high risk.

So while the concept of using these kinds of agents is interesting, I don't think we are quite there yet, both in terms of having the techniques for monitoring their efficacy in the chemopreventive setting, short of Phase III trials, which are even more onerous than in the setting of advanced cancer. And so we are not quite there yet. That is the parting comment I would like to make.

DR. SAXMAN: And that will close this session. Thank you very much, Paul.

[Brief recess.]

DR. SAXMAN: Let's go ahead and proceed with the next summary session. The second breakout session, breakout session B, focuses on immunotherapy, biologics, and gene therapy. The chairpersons included Dr. Jack Roth, who is a professor and chairman of the University of Texas, M.D. Anderson Cancer Center. David Johnson was to be the other moderator, and had some flight difficulties, I understand, so very gracious Dr. David Parkinson, who is Vice President of Clinical Research and Development at Novartis helped co-chair the meeting.